Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

Abstract

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.

Hypothermia modulates myeloid cell polarization in neonatal hypoxic–ischemic brain injury

“…Furthermore, in view of the enormous heterogeneity of this cell population, sole Iba-1 immunoreactivity might not be suitable for conclusions about microglia/myeloid cell phenotype and function. This is supported by our gene expression analyses in sorted CD11b + cells and by several reports demonstrating that myeloid cell populations differ in morphology and inflammatory profile, not only depending on the time course of disease but also on brain regions [ 44 – 46 ].…”

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

“…Here, we demonstrate a biological basis possibly explaining the severe adverse outcome in inflammation-sensitized asphyxiated neonates. It is commonly believed that similar to the initiation of inflammation, resolution of inflammation is an active process in which inflammation-resolving cells like microglia and their cytokines are pivotal for the termination of the inflammatory response [ 61 ]; however, as much as inflammation is a pivotal process in fighting off many threatening conditions, when it is unresolved, it forms the basis of a wide range of persistent/chronic diseases and secondary damage mediated by the inflammatory response constantly disrupting the return to homeostasis [ 61 ].…”

Early Thalamic Injury After Resuscitation From Severe Asphyxial Cardiac Arrest in Developing Rats

“…Ablation of microglia using minocycline ameliorates histologic injury ( Tang et al, 2010 ), although impact may vary by cardiac arrest characteristics ( Janata et al, 2019 ). In other brain hypoxia-ischemia models, microglial activation has both protective ( Fleiss et al, 2021 ) and deleterious ( Yew et al, 2019 ) effects. Interestingly, activated microglia generate nitric oxide (NO) among multiple other neurotoxic substances ( Brown and Vilalta, 2015 ), and NO depolarizes primarily bursting nRT neurons in the thalamus ( Yang and Cox, 2008 ).…”